The goal of this project is to develop the fruit fly, Drosophila melanogaster, as a genetically tractable model system to investigate molecular mechanisms underlying human neuropsychiatric disorders that involve serotonin, such as schizophrenia and depression. We propose to treat flies with specific serotonergic psychotomimetic agents that produce an observable behavioral effect. As shown with most previously studied pathways, the molecular events linking serotonin receptor interactions to behavior are likely to be highly conserved between the fly and humans. The use of the fly to study these conserved neurochemical events brings into play extremely powerful genetic techniques to rapidly elucidate key pathways and molecules that otherwise could take years, at a substantially greater cost, to identify by traditional mammalian-based methods. Importantly, the fly is believed to express a functional ortholog of the mammalian 5-HT2 receptor, as well as orthologs of the mammalian 5-HT1A, 5-HT7, dopamine D1 and D2, GABA, NMDA, and metabotropic glutamate receptors, all of which have been strongly implicated in a variety of human neuropsychiatric disorders. Here, we propose investigations to characterize the: 1) behaviors, 2) circuitry, and 3) neuropharmacology of the Drosophila CNS serotonin system using molecular, genetic, and behavioral experiments to create a solid foundation for future research. These Drosophila studies, in combination with ongoing proposed mammalian target identification experiments, together form a novel systems-based approach to explore neurochemical events relevant to neuropsychiatric disorders in humans, and will be of great importance to facilitate the discovery of novel targets for therapeutics. Summary with respect to public health: Schizophrenia is a debilitating neuropsychiatric disorder that affects about one out of every 100 Americans at a cost to the U.S. economy of nearly $63 billion/year. New approaches towards understanding underlying schizophrenia mechanisms are urgently needed in order to further understand and treat this disease, as well as other psychiatric disorders. We propose to develop the fruit fly as a model system to study the underlying serotonin neurochemistry of these diseases. The development and utilization of this model system will lead to an enhanced discovery rate of novel targets for therapeutics to treat these conditions. [unreadable] [unreadable]